Intermediates for preparing semi-synthetic cephalosporins and processes relating thereto

Abstract

Phosphorylated penicillins and cephalsporins are described which are obtained by reacting a penicillin or cephalosporin with a trivalent or pentavalent phosphorus halide and treating the thus formed product sequently with an acid chloride, an alcohol and water to form a phosphorylated anhydride of a 6-aminopenicillanic acid or 7-aminocephalosporanic acid salt, respectively, and thereafter acylating the thus formed product and splitting off the carboxyl protective group to obtain the desired penicillin or cephalosporin compound.

What is claimed is: 
     
       1. A hydrohalide salt of the formula: ##STR29## wherein: R is selected from the class consisting of hydrogen, (lower) alkanoyloxy containing 2 to 8 carbon atoms, phenoxy, naphthoxy and a quaternary ammonium radical; R 1  and R 2  are selected from the class consisting of (lower)alkoxy, (lower)alkylthio, phenyl, naphthyl, phenoxy, naphthoxy, halo, phenylthio, phenyl(lower)alkyl, phenyl(lower)alkylthio, phenyl(lower)alkoxy, (lower)alkyl, halo(lower)alkyloxy, a radical of the formula ##STR30## R 1  and R 2  when joined together form with the phosphorus atom the ring ##STR31## R 3  is the oxygen atom which when present is linked by a double bond to the phosphorus atom; X is selected from the class consisting of oxygen, sulfur and methylene; R 4  is selected from the class consisting of hydrogen and (lower)alkyl; n is an integer from 0 to 1; m is an integer from 1 to 6. 
     
     
       2. The hydrohalide salt of the formula: ##STR32## wherein: R 4  is selected from the class consisting of hydrogen and lower alkyl; and m is an integer from 1 to 6. 
     
     
       3. A compound according to claim 2 which is the hydrochloride salt of 7-aminocephalosporanic acid, 1,3,2-dioxaphospholan-2-yl ester. 
     
     
       4. A compound according to claim 2 which is the hydrochloride salt of 7-aminodesacetoxycephalosporanic acid, 1,3,2-dioxaphospholan-2-yl ester. 
     
     
       5. A process for preparing a semi-synthetic cephalosporin which comprises: a. reacting a cephalosporin compound of the formula ##STR33## with a phosphorylating agent of the formula ##STR34## to produce a compound of the formula ##STR35## said reaction being carried out under anhydrous conditions in the presence of an inert non-hydroxylic organic solvent and a tertiary amine at a temperature in the range of about -40° C to about +10° C, the molar ratio of said cephalosporin compound to said phosphorylating agent being about 0.5:1 to about 3:1;   b. reacting said compound obtained in step (a) with an acid chloride in the presence of a tertiary amine at a temperature between about -10° C and -65° C to produce an imino chloride compound of the formula ##STR36## c. reacting said imino chloride with an alcohol at a temperature below about -10° C to produce an imino ether of the formula ##STR37## d. reacting said imino ether with water at a temperature below about -20° C and treating the resulting compound with a reactive derivative of an organic carboxylic acid in the presence of a tertiary amine at a temperature between about 0° C and -60° C to produce a compound of the formula ##STR38## e. and hydrolyzing the resulting acylated product to remove the carboxyl protective group and obtain a semi-synthetic cephalosporin; wherein:     M is selected from the class consisting of hydrogen, an alkali metal and a tertiary amine; R is selected from the class consisting of hydrogen (lower)alkanoyloxy containing 2 to 8 carbon atoms, phenoxy, naphthoxy and a quaternary ammonium radical; R 16  is selected from the class consisting of 2-thienylmethyl and 4-amino-4-carboxy-n-butyl; R 4  is selected from the class consisting of hydrogen and lower alkyl; R a  is selected from the class consisting of lower alkyl, phenyl(lower)alkyl, cycloalkyl of 4 through 8 carbon atoms, phenoxy(lower)alkyl, (lower)alkoxy, (lower)alkyl; and m is an integer from 1 to 6.   
     
     
       6. A process for preparing a semi-synthetic cephalosporin which comprises: a. reacting a compound of the formula: ##STR39## with a phosphorylating agent of the formula ##STR40## in the presence of an acid binding agent and an inert, non-hydroxylic organic solvent at a temperature between about -40° C and about +10° C to obtain a compound of the formula: ##STR41## b. reacting an acid halide with a compound obtained in step (a) in the presence of an acid binding agent at a temperature below 0° C to produce the corresponding imino halide;   c. reacting said imino halide compound with a alcohol at a temperature below about -10° C to convert said imino halide compound to the hydrohalide salt of the corresponding imino ether compound; d. converting said imino ether compound by hydrolysis at a temperature below about -20° C to the hydrohalide salt of a compound of the formula ##STR42## e. reacting a compound formed in step (d) with an acylating agent selected from an organic carboxylic acid and a functional reactive derivative of such acid in the presence of an acid binding agent to obtain acylation of the amino group; and   f. treating said acylated compound with sufficient water to obtain a compound of the following formula: ##STR43## and the corresponding acid addition salt where a free amino group is present on the acyl radical, wherein:   M is selected from the class consisting of hydrogen, an alkali metal and a tertiary amine; R is selected from the class consisting of hydrogen, (lower)alkanoyloxy containing 2 to 8 carbon atoms, phenoxy, naphthoxy and a quaternary ammonium radical; R 16  is a substituent selected from those contained in a natural and semi-synthetic cephalosporin; R 1  and R 2  are selected from the class consisting of (lower)alkoxy, (lower)alkylthio, phenyl, naphthyl; phenoxy, naphthoxy, phenylthio, phenyl(lower)alkyl, phenyl(lower)alkylthio, halogen, lower alkyl, halo(lower)alkyl, halo(lower)alkyl, halo(lower)alkyloxy, a radical of the formula ##STR44## R 1  and R 2  when joined together form with the phosphorus atom the ring ##STR45## R 3  is the oxygen atom which when present is linked by a double bond to the phosphorus atom; X is selected from the class consisting of oxygen, sulfur and methylene; R 4  is selected from the class consisting of hydrogen and (lower)alkyl; n is an integer from 0 to 1; m is an integer from 1 to 6.   
     
     
       7. A process according to claim 6 wherein said phosphorylating agent is selected from the class consisting of 2-chloro-1,3,2-dioxaphospholane and 2-chloro-1,3,2-dioxaphosphorinane. 
     
     
       8. A process according to claim 7 wherein said acylating agent is selected from the class consisting of D(-)phenylglycyl chloride hydrochloride and 2-thienylacetic acid chloride. 
     
     
       9. A process according to claim 6 wherein said phosphorylating agent is phosphorus trichloride. 
     
     
       10. A process according to claim 6 wherein R 16  is selected from the class consisting of 2-thienylmethyl and 4-amino-4-carboxy-n-butyl. 
     
     
       11. A process according to claim 6 wherein said phosphorylating agent is ##STR46## 
     
     
       12. A process according to claim 6 wherein R 16  is a substituent contained in a natural cephalosporin. 
     
     
       13. A process which comprises reacting a hydrohalide salt of 7-aminocephalosporanic acid, 1,3,2-dioxaphospholan-2-yl-ester with phenylglycylchloride, hydrochloride in the presence of a tertiary amine and a non-hydroxylic organic solvent at a temperature of about 0° to -60° C., and treating the resulting product with water to produce the hydrochloride salt 7-(α-aminophenylacetamido)cephalosporanic acid. 
     
     
       14. A process for preparing a semi-synthetic cephalosporin which comprises reacting a hydrohalide salt of a compound of the formula: ##STR47## with an acylating agent which is an organic carboxylic acid or a reactive derivative thereof in the presence of an acid binding agent and thereafter treating the resulting product with water to produce an acid addition salt of a compound of the formula ##STR48## wherein: R is selected from the class consisting of hydrogen (lower)-alkanoyloxy containing 2 to 8 carbon atoms, phenoxy, naphthoxy and a quaternary ammonium radical; R 1  and R 2  are selected from the class consisting of halogen, (lower)alkoxy, (lower)alkylthio, phenyl, naphthyl, phenoxy, naphthoxy, phenylthio, phenyl(lower)alkyl, phenyl(lower)alkylthio, phenyl(lower)alkyloxy, (lower)alkyl, halo(lower)alkyloxy, a radical of the formula ##STR49## R 1  and R 2  may be joined together to form with the phosphorus atom the ring ##STR50## R 3  is the oxygen atom which when present is linked by a double bond to the phosphorus atom; R 4  is selected from the class consisting of hydrogen and (lower)alkyl; X is selected from the class consisting of oxygen, sulfur and methylene; n is an integer from 0 to 1; m is an integer from 1 to 6.